Benzene derivatives

ABSTRACT

Benzene derivatives of the formula:   D R A W I N G WHEREIN R4 represents, for example, a hydroxy group, or an optionally substituted ureido or thioureido group, which possess similar pharmacodynamic properties.   WHEREIN R1 represents alkanoylamino of not more than nine carbon atoms, R2 represents alkyl of one through six carbon atoms, and R3 represents alkyl of one through six carbon atoms or cycloalkyl of three through six carbon atoms, possess pharmacodynamic properties and are useful in the treatment of various cardiac disorders. Moreover, they can be used as starting materials for corresponding compounds in which the ketone group -COR2 is replaced by a grouping

United States Patent 1 Wooldridge et al.

[ Apr. 10, 1973 BENZENE DERIVATIVES [75] Inventors: Kenneth Robert Harry Wooldridge,

Brentwood; Berkeley Basil, Highwood, Near Chelmsford, both of England [73] Assignee: May & Baker Limited, Dagenham,

Essex, England [22] Filed: Dec. 19, 1968 [21] Appl. No.: 785,403

[30] Foreign Application Priority Data Dec. 22, 1967 Great Britain ..58,5 16/67 May 14, 1968 Great Britain ..56,5l3/68 Aug. 2, 1968 Great Britain ..37,103/67 [52] US. Cl. ..260/562 A, 260/348 A, 260/479 R, 260/50l.l7, 260/501.l8, 260/552 R, 260/553 R, 424/324 [5 l 1 Int. Cl ..C07e 103/38 [58] Field of Search ..260/562 [56] References Cited UNITED STATES PATENTS 3,408,387 10/1968 Howe et al. ..260/482 Primary Examiner-Harry l. Moatz Attorney-Stevens, Davis, Miller & Mosher ABSTRACT Benzene derivatives of the formula:

OOHCHCH2NHR3 wherein R represents alkanoylamino of not more than nine carbon atoms, R represents alkyl of one through six carbon atoms, and R represents alkyl of one through six carbon atoms or cycloalkyl of three through six carbon atoms, possess pharmacodynamic properties and are useful in the treatment of various cardiac disorders. Moreover, they can be used as starting materials for corresponding compounds in which the ketone group COR is replaced by a grouping I It wherein R represents, for example, a hydroxy group, or an optionally substituted ureido or thioureido group, which possess similar pharmacodynamic properties.

7 Claims, No Drawings ll BENZENE DERIVATIVES This invention relates to new benzene derivatives.

According to the present invention there are provided the new benzene derivatives of the general formula:

wherein R represents a straightor branched-chain alkanoylamino group containing not more than nine (preferably not more than six) carbon atoms, R represents an alkyl group, and R represents an alkyl group, or a cycloalkyl group containing from three to six carbon atoms, and their acid addition salts.

In this specification it is to be understood that the alkyl groups represented by the symbols R and R contain not more than six carbon atoms and may have straightor branched-chains.

The compounds of general formula I exist in stereoisomeric forms and the present invention includes all such forms, and mixtures thereof, and their acid addition salts.

The new benzene derivatives of formula I and their non-toxic acid addition salts possess pharmacodynamic properties of value in the treatment or prophylaxis of various cardiac disorders manifested by angina pectoris and cardiac arrhythmias and, administered in conjunction with a sympathetic a-receptor blocking agent, in the relief, prior to surgery, of the symptoms of pheochromocytoma which are due, as is known, to the presence of high amounts of noradrenaline in the blood stream.

In laboratory screening methods, the new compounds inhibit sympathetic B-receptors in the rat, guinea-pig, cat and dog at doses which do not inhibit sympathetic a-receptors or have other untoward cardiovascular actions. In addition, the compounds show a specificity of action in that they have a substantial blocking action on cardiac Q-receptors at dosages substantially lower than those required to have a substantial blocking action on sympathetic B-receptors in bronchial muscle and the vascular system. This property is of particular value in the treatment of conditions in which blocking sympathetic B-receptors in the bronchi is contraindicated, e.g. in bronchial asthma and various forms of bronchospasm.

For example, (I) the new compounds block the cardiac sympathetic ,B-receptors in the guinea-pig at doses between 0.01 and 0.1 mg./kg. animal body weight administered intravenously, which are lower than those required to inhibit sympathetic B-receptors on bronchial muscle as determined by their ability to reduce isoprenaline-induced bronchodilatation at doses between 0.15 and 3.0 mg./kg. animal body weight administered intravenously and the absence of potentiation of anaphylactic bronchospasm in this species at doses below 5 mg./kg. animal body weight administered intravenously. (II) The compounds also show specificity of action in the cat anaesthetized with a mixture of chloralose and pentobarbital sodium administered intraperitoneally as shown by their inhibition (at doses between 0.025 and 0.1 mg./kg. animal body weight administered intravenously) of the positive chronotropic effects upon cardiac muscle of intravenously administered isoprenaline and by their inhibition (at doses between 0.05 and 0.2 mg./kg. animal body weight administered intravenously) of the effects of accelerans nerve stimulation, as compared with their inhibition (at doses between 0.15 and 3.0 mg./kg. animal body weight administered intravenously) of the fall in diastolic pressure produced by intravenously administered isoprenaline and their inhibition (at doses between 0.5 and 2.0 mg./kg. animal body weight administered intravenously) of the bronchodilatation produced by intravenously administered isoprenaline. (Ill) A specificity of action on sympathetic B-receptors is also shown by the new compounds in experiments carried out in the dog anaesthetized with intravenously administered pentobarbital sodium as shown by their effect in inhibiting (at doses between 0.01 and 0.1 mg./kg. animal body weight administered intravenously) the positive inotropic and chronotropic effects upon cardiac muscle of intravenously administered isoprenaline and in inhibiting (at doses between 0.02 and 0.2 mg./kg. animal body weight administered intravenously) the effects of accelerans nerve stimulation, which doses are lower than the doses required (0.2 to 2.0 mg./kg. animal body weight administered intravenously) to inhibit the fall in diastolic pressure produced by intravenously administered isoprenaline. (IV) In addition, the new compounds correct experimentally induced cardiac arrhythmias. For example, in the cat anaesthetized with a mixture of chloralose and pentobarbital sodium administered intraperitoneally and in the dog anaesthetized with pentobarbital sodium administered intravenously, reversal of the ventricular tachycardia produced by the intravenous administration of ouabain and a return to normal sinus rhythm is obtained at doses between 3.0 and 30 mg./kg. animal body weight administered intravenously. They also increase the refractory period of isolated rabbit atria to electrical stimulation by the method described by 6.8. Dawes, Br. J. Pharmac. Chemother, l, (1946) in concentrations comparable to the concentrations of quinidine which produce a similar increase in the refractory period.

The compound propranolol, which is used clinically in the treatment or prophylaxis of angina pectoris and cardiac arrhythmias and, administered in conjunction with a sympathetic a-receptor blocking agent, in the relief, prior to surgery, of the symptoms of pheochromocytoma, gives similar results in these tests but does not show specificity of action on cardiac as opposed to bronchial sympathetic B-receptors' The benzene derivatives of formula I wherein R is an alkanoylamino group containing not more than six carbon atoms are also useful as starting materials for the preparation of corresponding compounds of the aforesaid formula but in which the ketone group COR is replaced by a grouping (wherein R represents, for example, a hydroxy, ureido, alkylureido, hydroxyalkylureido, alkoxyalkylureido, thioureido, alkylthioureido, hydroxyalkylthioureido, alkoxyalkylthioureido, heterocyclylureido or heterocyclylcarbonylamino group, and R is as hereinbefore defined), which compounds are described in and included within the claims of the specification of our copending application Ser. No. 729,394 filed May 15, 1968, and possess similar pharmacodynamic properties to those mentioned above in respect of the benzene derivatives of general formula 1.

Preferred compounds of the present invention for the treatment of cardiac disorders are the compounds of general forumla 1 wherein R represents an alkyl group, especially those compounds in which R represents an isopropyl group, and more particularly 5 -acetamido-2 2-hydroxy-3-isopropylaminop ropoxy)acetophenone, 2'-(2-hydroxy-3- isopropylaminopropoxy )-5 propionamidopropiophenone and 5-butyramido-2- (2-hydroxy-3-isopropylaminopropoxy)acetophenone and their non-toxic acid addition salts.

According to a feature of the present invention, the compounds of general formula 1 are prepared by the reaction of an epoxide of the general formula:

(wherein R and R are as hereinbefore defined, and M represents a hydrogen or alkali metal atom) in an aquehereinbefore defined) in an inert organic solvent such as dimethylfonnamide or a lower alkanol (e.g. methanol or ethanol) at a temperature between 0C. and 100C. I

The epoxides of general formula 11 may be prepared by known methods for the preparation of epoxides, e.g. by the reaction of epichlorohydrin with a phenol of the general formula:

III

(wherein R and R are as hereinbefore defined, and M represents a hydrogen or alkali metal atom) in an aqueous or inert organic solvent, such as dimethylforrnamide or a lower alkanol (e.g. ethanol), at a temperature between 0C. and 100C. When M represents a hydrogen atom, the reaction is carried out in the presence of a basic condensing agent (e.g. potassium carbonate, sodium hydroxide or sodium ethoxide).

Compounds of general formula 111 wherein M represents an alkali metal atom may be prepared by known methods for the preparation of alkali metal derivatives of phenols, for example by treating a compound of general formula III wherein M represents a hydrogen atom with a solution of an alkali metal alkoxide (e.g. sodium ethoxide) in a lower alkanol (e.g. ethanol).

Compounds of general formula 111 wherein M represents a hydrogen atom may be prepared by known methods such as heating an ester of the general formu- 1a:

OOCR

1 R I V (wherein R and R are as hereinbefore defined) with a catalyst, for example aluminium chloride, at a temperature between 130C. and 180C., optionally in the presence of an inert organic solvent such as 1,l,2,2- tetrachloroethane.

Compounds of general formula IV may be prepared by known methods for the preparation of esters of p-alkanamidophenols.

The compounds of general formula 1 may be converted into acid addition salts by known methods, e.g. by the action of an acid on the compounds of general formula I in an appropriate solvent such as diethyl ether. The acid addition salt which is formed is precipitated, if necessary after concentration of its solution, and is separated by filtration or decantation.

For use in medicine, the compounds of general formula l are employed as such or in the form of non-toxic acid addition salts (i.e. salts containing anions which are non-toxic at the dosages used) such as salts derived from inorganic acids (e.g. hydrochlorides, hydrobromides, phosphates, sulphates and nitrates) and from organic acids (e.g. oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-firnl.) gentisates and D-di-ptoluoyl-tartrates). pressure By the term known methods as used in this specification is meant methods heretofore used or described in the literature.

The following Examples illustrate the preparation of compounds of the present invention.

EXAMPLE 1 A mixture of 5'-acetamido-2'-(2,3-epoxypropoxy)acetophenone (17 g.) isopropylamine ml.), and dry ethanol (100 ml.) was heated under reflux for 24 hours. The excess of isopropylamine and ethanol was evaporated and the residue was dissolved in chloroform. The solution was extracted with dilute hydrochloric acid and the acid extract was made a1- kaline with sodium hydroxide and then extracted with chloroform. The chloroform solution was dried and evaporated. The residue was treated with light petroleum and the solid obtained was recrystallised from ethyl acetate to give 5'-acetamido-2'-(2-hydroxy-3- isopropylaminopropoxy)acetophenone, m.p. 131-l34 "C The 5-acetamido-2-(2,3-epoxypropoxy)acetophenone used as starting material was prepared as follows:

5-Acetamido-2-hydroxyacetophenone (19.6 g., prepared according to M. Julia & M. Baillarge, Bull. Soc. chim. FL, 1952, 639) was dissolved in the minimum amount of dry ethanol. A solution of sodium ethoxide, prepared from sodium (2.3 g.) and ethanol, was added and the solid which separated was removed by filtration, washed with a little dry diethyl ether and dried in a vacuum-desiccator overnight. The solid was placed in a Soxhlet extractor and a boiling solution of epichlorohydrin (28.3 g.) in ethanol was used to extract the solid overnight. Diethyl ether was added to the cooled solution, the sodium chloride was filtered off and the filtrate was evaporated. The residue was extracted with benzene and the extract evaporated to give 5 '-acetamido-2'-(2,3-epoxypropoxy)acetophenone, m.p. -112C.

EXAMPLE 2 2'-(2,3-Epoxypropoxy)-5- propionamidoacetophenone (7 g.), isopropylamine (40 g.) and methanol (200 ml.) were heated together under reflux for 1 /2 hours. The reaction mixture was concentrated under reduced pressure and the residual oil was treated with N hydrochloric acid and ethyl acetate. The acid extract was brought to pH 11 with 2N aqueous sodium hydroxide solution and then extracted with chloroform. The dried chloroform extract was concentrated to give an oil, which was treated with diethyl ether to give 2-(2-hydroxy-3-isopropylaminopropoxy)-5-propionamidoacetophenone (5.5 g.), m.p.

The following compounds were prepared similarly:

2'-(2-hydr0xy-3-isopropylaminopropoxy)-5isobutyramidoacetophenone, m.p. 102104C., from 2'-(2,3-epoxypropoxy)-5' isobutyramidoacetophenone;

2-(2-hydroxy-3-isopropylaminopropoxy)-5- valeramidoacetophenone, m.p. l29-13 1C., from 2-(2,3-epoxypropoxy)-5'- valeramidoacetophenone; 2'-(2-hydroxy-3-isopropylamin0propoxy)-5'- isovaleramidoacetophenone, m.p. 1 l01 1 1C., from 2-(2,3-epoxypropoxy)-5- isovaleramidoacetophenone; 5-hexanamido-2-(2-hydroxy-3- isopropylaminopropoxy)acetophenone, m.p. 141142C., from 2(2,3-epoxypropoxy)-5'-hexanamidoacetophenone; 2-(2-hydroxy-3-isopropylaminopropoxy)-5-octanamidoacetophenone, m.p. 1l7l19C., from 2'-(2,3-epoxypropoxy)-5-octanamidoacetophenone, 2-(2-hydroxy-3-isopropylaminopropoxy)-5'- nonanamidoacetophenone, m.p. 108109C., from crude 2'-(2,3-epoxypropoxy)-5- nonanamidoacetophenone;

5 '-butyramido-2'-( 2-hydroxy-3- methylaminopropoxy)acetophenone, 143l465-butyramido-2-(2,3-epoxypropoxy)acetophenone (prepared as described in Example 4), and

2 3-tert-butylamino-2-hydroxypropoxy )-5 '-butyramidoacetophenone, m.p. 138C., from 5-butyramido-2 2,3-epoxypropoxy )acetophenone (prepared as described in Example 4).

propionamidoacetophenone used as starting material was prepared as follows:

p-Propionamidophenol (82 g.; prepared according to Fierz-David and Kuster, Helv. chim. Acta, 1939, 22, 82), acetyl chloride (40 g.) and benzene (1 litre) were heated under reflux until a solution formed (1 hour). This solution was cooled and added to water and the precipitated solid was removed by filtration, washed with water and dried to give p-propionamidophenyl acetate (50 g.), m.p. 100105C. A mixture of ppropionamidophenyl acetate (50 g.) and aluminium chloride (100 g.) was heated at 170C. for 5 hours. An excess of water was added to the cooled mixture and the solid residue was removed by filtration and recrystallised from aqueous ethanol to give 2'-hydroxy- 540 -propionamidoacetophenone (16 g.), m.p. 1 16120C. A solution of 2-hydroxy-5'- propionamidoacetophenone (11.5 g.) in ethanol (200 ml.) was added to an ethanolic solution of sodium ethoxide prepared from sodium (1.27 g.) and ethanol (200 ml.). The resulting solution was evaporated to dryness under reduced pressure. Benzene was added and the solution was again evaporated to dryness under reduced pressure. Dimethylformamide ml.) and epichlorohydrin (20 ml.) were added and the solution was heated at 100C. for 4 hours. The solution was concentrated under reduced pressure to give an oil which was then treated with water to give a solid which was recrystallised from ethyl acetate to give 2'-(2,3-epx- 'oypropoxy)-5-propionamidoacetophenone (7.1 g.),

m.p. 125C.

The following compounds were prepared similarly: 2'-(2,3-epoxypropoxy)-5-isobutyramidoacetophenone, m.p. l23-l27C., from 2 -hydroxy-5 '-isobutyramidoacetophenone; 2'-(2,3-epoxypropoxy)-5'-valeramidoacetophenone,

m.p. 137- 1 39C., from 2-hydroxy-5 valeramidoacetophenone; 2'-(2,3-epoxypropoxy)- 5-isovaleramidoacetophenone, m.p. 95-100C., from 2'-hydroxy-5 '-isovaleramidoacetophenone; 2'-( 2,3-epoxypropoxy )-5 -hexanamidoacetophenone, m.p. l36-137C., from 5-hexanamido-Z-hydroxyacetophenone; 2-(2,3-epoxypropoxy)-5-octanamidoacetophenone, m.p. 133l34C., from 2'-hydroxy-5 -octanamidoacetophenone, and crude 2'-(2,3-epoxypropoxy )-5 nonanamidoacetophenone from 2-hydroxy-5'- nonanamidoacetophenone. The intermediate 2-hydroxy-5'-isobutyramidoacetophenone was prepared as follows:

lsobutyric anhydride (17.5 g.) was added dropwise with stirring to a mixture of 5'-amino-2'-hydr0xyacetophenone (13.7 g.; prepared according to M. Julia & M. Baillarge, Bull, Soc. chim. Fr., 1952, 639), isobutyric acid (10 g.), and water (25 ml.) which was heated on the steam-bath. Heating and stirring were continued for a further 1 hour, and the mixture was cooled. After the addition of a further quantity (25 ml.) of water, a solid separated. This was filtered off, dried, and triturated with diethyl ether. The solid was filtered off and dried to give 2'-hydroxy-5'-isobutyramidoacetophenone (14.15 g.), m.p. l3 ll 32C.

The following compounds were prepared similarly:

2-hydroxy-5'-valeramidoacetophenone, m.p.

2-hydroxy-5 -isovaleramidoacetophenone, m .p.

5 '-hexanamido-2-hydroxyacetophenone, m.p.

2 '-hydroxy-5 -octanamidoacetophenone m .p.

1081 10C., and

2-hydroxy-5-nonanamidoacetophenone, m.p.

EXAMPLE 3 2'-(2,3-Epoxypropoxy)-5- propionamidopropiophenone (14 g.), isopropylamine (80 g.) and methanol (200 ml.) were heated together under reflux for 1 /2 hours. The reaction mixture was then concentrated under reduced pressure to give a residual oil which was recrystallised from ethyl acetate to give 2-(2-hydroxy-3-isopropylaminopropoxy)-5- propionamidopropiophenone (13 g.), m.p. 8992C.

2-(2,3-Epoxypropoxy)-5'- propionamidopropiophenone used as starting material was preapred as follows:

solution of 2 -hydroxypropionamidopropiophenone (30 g.; prepared according to Raval and Thakor, J. Indian Chem. Soc. 1961, 38, 421) in ethanol (200 ml.) was added to an ethanolic solution of sodium ethoxide prepared from sodium (3.12 g.) and ethanol (200 ml.). The resulting solution was evaporated to dryness under reduced pressure. Benzene was added and the solution was again evaporated to dryness under reduced pressure. Dimethylformamide (200 ml.) and epichlorohydrin (50 ml.) were added and the solution was heated at 100C. for 4 hours. The solution was concentrated under reduced pressure to give an oil which was then treated with water to give a solid which was recrystallised from ethyl acetate to give 2'-(2,3-epoxypropoxy)- 5-propionamidopropiophenone (18.4 g.), m.p. 1l4-l18C.

EXAMPLE4 Crude 5 '-butyramido-2 2,3 -epoxypropoxy)acetophenone (16 g.), isopropylamine g.) and ethanol (100 ml.) were heated together under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the residual oil was dissolved in N hydrochloric acid. The acid solution was extracted with ethyl acetate, the ethyl acetate layers being discarded. The acidic solution was brought to pH 11 with 2N aqueous sodium hydroxide solution and then extracted with chloroform. The dried chloroform extracts were concentrated under reduced pressure to give an oil which was crystallised from a mixture of ethanol and diethyl ether to give 5-butyramido-2'-(2- hydroxy-3-isopropylaminopropoxy)acetophenone (3 g.), m.p. ll9-123C.

Similarly prepared was 5'-butyramido-2-(3- cyclohexylamino-2-hydroxypropoxy)acetophenone, m.p. 112-113C.

Crude 5 -butyramido-2 2,3 -epoxypropoxy)acetophenone used as starting material was prepared as follows:

p-Butyramidophenol (58 g.; prepared according to Fierz-David and Kuster, loc.cit.), acetyl chloride (25.4 g.) and benzene (500 ml.) were heated together under I reflux until a solution formed (12 hours). This solution was cooled and treated with water. The benzene layer was separated and the aqueous layer was again extracted with benzene.

The combined benzene extracts were dried and evaporated to dryness under reduced pressure to give p-butyramidophenyl acetate (38 g.) as an off-white solid, m.p. l02-103C. A mixture of p-butyramidophenyl acetate (38 g.), aluminium chloride 7 (80 g.) and l,1,2,2,-tetrachloroethane (250 ml.) was solution was extracted with chloroform and the chloroform extract was dried and concentrated under reduced pressure to give 5-butyramido-2'-hydroxyacetophenone (15.6 g.), m.p. ll4-1 17C. A solution of 5'-butyramido-2'-hydroxyacetophenone (15 .6 g.) in ethanol 100 ml.) was added to an ethanolic solution of sodium ethoxide which was prepared from sodium (1.62 g.) and ethanol (100 ml.) The resulting solution was evaporated to dryness under reduced pressure and dimethylformamide (100 ml.) was added to the solid residue. Approximately 10 ml. of dimethylformamide was removed by distillation under reduced pressure. Epichlorohydrin (25 ml.) was added and the solution was heated at 100C. for 4 hours. The solution was concentrated under reduced pressure to give a residual oil which was treated with water to give a solid. The solid was dissolved in ethanol and the resulting solution was treated with charcoal, filtered and concentrated under reduced pressur to give crude 5'-butyramido-2'-(2,3- epoxypropoxy)acetophenone (16 g.), m.p. l10-1l6 O The crude compound may be purified by recrystallisation from ethyl acetate, after treatment with decolourizing charcoal, to give pure 5'-butyramido-2- (2,3-epoxypropoxy)acetophenone, m.p. 136-138C.

EXAMPLE 5 5 -Butyramido-2 2-hydroxy-3- isopropylaminopropoxy)acetophenone (3.36 g.; prepared as described in Example 4) was dissolved in anhydrous methanol (50 ml.), and anhydrous diethyl ether (200 ml.) added. A saturated solution of anhydrous hydrogen chloride in anhydrous diethyl ether (25 ml.) was added dropwise with stirring. An oil was precipitated, which crystallized on further stirring. The solid was filtered off and recrystallized from a mixture of anhydrous methanol and anhydrous diethyl ether to give 5'-butyramido-2-( 2-hydroxy-3- isopropylaminopropoxy)acetophenone hydrochloride (2.5 g.),m.p.141143C.

EXAMPLE 6 Boiling solution of 5-butyramido-2'-(2-hydroxy-3- isopropylaminopropoxy)acetophenone (3.36 g.; prepared as described in Example 4) in acetone (250 ml.) and of D-tartaric acid (1.5 g.) in acetone (50 ml.) were mixed, and the mixture allowed to cool overnight. The solid which separated was filtered off to give 5 '-butyramido-2'-( 2-hydroxy-3-isopropylaminopropoxy)acetophenone D-tartrate (3.7 g.), m.p. ll79C.

The present invention includes within its scope pharmaceutical compositions which comprise at least one of the benzene derivatives of general formula I, or a non-toxic acid addition salt thereof, in association with a pharmaceutically acceptable carrier or coating. In clinical practice the compounds of the present invention will normally be administered orally or parenterally.

Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, at least one of the active compounds is mixed with at least one inert diluent such as starch, sucrose or lactose. As is normal practice the compositions may also contain additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents such compositions may also contain adjuvants, such as wetting and susepending agents, and sweetening, flavouring, perfuming and preserving agents. According to the invention, the compounds for oral administration also include capsules of absorbable material, such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example by filtration through a bacteria-retaining filter, by incorporation of sterilising agents in the compositions, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

The percentage of active ingredient in the compositions of the invention may be varied so that a suitable dosage is obtained. Obviously, several unit dosage forms may be administered at about the same time. The dosage employed depends upon the desired therapeutic effect, the route of administration and the duration of the treatment. In the adult, the doses are generally between 0.1 and 0.5 mg./kg. body weight per day by intravenous administration. However, the new compounds will usually be self-administered by the patient and oral administration is therefore preferred, by which route of administration the doses are generally between 1 and 10 mg./kg. body weight per day in the adult.

The following Examples illustrate pharmaceutical compositions according to the invention.

EXAMPLE 7 Tablets of the formula:

2'-(2-hydroxy-3-isopropylaminopropoxy) -5-propionamidopropiophenone 20 mg. lactose 49.5 mg. starch 20 mg. dextrin 20 mg. magnesium stearate 0.5 mg.

EXAMPLE 8 An injectable solution of the following composition:

2-(2-hydroxy-3-isoprop laminopropoxy)-5'- propionamidopropiop enone hydrochloride distilled water up to ml.

was prepared by dissoliving the amine hydrochloride in the distilled water. The solution was filtered and filled into ampoules which were sterilized in an autoclave.

EXAMPLE 9 Tablets of the fomrula:

5'-butyramido-2-(2-h droxy-3-isopropyl aminopropoxy)acetop enone 20 mg. lactose 49.5 mg. starch 20 mg. dextrin 20 mg. magnesium stearate 0.5 mg.

wherein R represents alkanoylamino of one through nine carbon atoms, R represents alkyl of one through six carbon atoms, and R represents alkyl of one through six carbon atoms or cycloalkyl of three through six carbon atoms, and non-toxic acid addition salts thereof.

2. A compound according to claim 1 wherein R represents alkanoylamino of one through six carbon atoms.

3. A compound according to claim 1 wherein R represents alkyl of one through six carbon atoms.

4. A compound according to claim 1 wherein R represents isopropyl.

5. The compound according to claim 1 which is 5'- acetamido-2'-(2-hydroxy-3-isopropylaminopropoxy)acetophenone, and non-toxic acid addition salts thereof.

6. The compound according to claim 1 which is 2'-(2 hydroxy 3 isopropylaminopropoxy)-5-bropiophenone, and non-toxic acid addition salts thereof.

7. The compund according to claim 1 which is 5-butyramido-2-(2-hydroxy-3-isopropylaminopropoxy)acetophenone, and non-toxic acid addition salts thereof.

UNITED sTATEs PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 3,726,919 DATED I April 10, 1973 |NVENTOR(S) Wooldridge et a1 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Under [30] Foreign Application Priority Data", the number of the third British application should be changed from "37,103/67" to --37,l03/68.

Signed and Scaled this Nineteenth of June I979 [SEAL] Attest:

RUTH C M SON DONALD W. BANNER Attestillg Oflicer' Commissioner of Patents and Trademarks UNITED STATES PATENT OFFICE CERTWIQATE @F .CQECTEQN Patent No. 3,726 919 Dated April 10, 1973 lnventofls) Kenneth Robert Harry WOOLDRIDGE et al It is certified that error appears in the above-identified patent and that said Letters Patentare hereby corrected as shown below:

Title Page Clarify the double bond between the carbon and nitrogen atoms in the second formula drawing; Col. 3, lines 29 Amend to read: (wherein R and R are as hereinbefore defined) with an amine of general formula R NH (wherein R is as hereinbefore defined) in an inert organic i solvent such";

"Col. 4, lines 25 Amend to read: "maleates, methylene-bis-fl j and 26, -hydroxynapthoates, gentisates and D-di-pi toluoyl-tartrates)."-;

Col, 4, line 37, Insert after "(l7g.)";

Col, 5, line 43, Amend to read: "l43l46C. from 5- butyramidos-Z (2, 3-epox-"y Col. 5, line 66, Replace "540" by "5"; I

Col. 8, line 19, Replace "pressur" by "pressure";-

-Col. 8, line 44, Replace "solution" by "solutions";

Col, 10, line 9, Replace "dissoliving" by "dissolving";

Col. 10, line 25, Replace "mangesium" by "magnesium";

Col, 10, Claim 6, Replace "5'-bro" by "-5 line 2, propionamidopro-" Signed and sealed this 29th day of" January 1971p,

(SEAL) Attest:

EDWARD M.FLETCHER,JR., RENE D, TEGTMEYER Attesting Officer 7 Acting Commissioner of Patents 

2. A compound according to claim 1 wherein R1 represents alkanoylamino of one through six carbon atoms.
 3. A compound according to claim 1 wherein R3 represents alkyl of one through six carbon atoms.
 4. A compound according to claim 1 wherein R3 represents isopropyl.
 5. The compound according to claim 1 which is 5''-acetamido-2''-(2-hydroxy-3-isopropylaminopropoxy)acetophenone, and non-toxic acid addition salts thereof.
 6. The compound according to claim 1 which is 2''-(2-hydroxy-3-isopropylaminopropoxy)-5''-propionamidopropiophenone, and non-toxic acid addition salts thereof.
 7. The compund according to claim 1 which is 5''-butyramido-2''-(2-hydroxy-3-isopropylaminopropoxy)acetophenone, and non-toxic acid addition salts thereof. 